Purpose: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methlyguanine-DNA-methlytransferase (MGMT) promoter. Patients and Methods: Patients (n=257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n=111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A non-comparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Pre-specified post hoc analyses of markers reflecting target activation were performed. Results: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% CI (58.2-82.2)] in the temozolomide arm and 69.6% [95% CI (55.8-79.9)] in the temsirolimus arm [HR=1.16, 95% CI (0.77-1.76), p=0.47]. In multivariable prognostic analyses of clinical and molecular factors phosphorylation of mTORSer2448 in tumor tissue (HR=0.13, 95% CI (0.04-0.47), p=0.002), detected in 37.6%, was associated with benefit from temsirolimus. Conclusions: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition.
- Received December 28, 2015.
- Revision received February 26, 2016.
- Accepted April 3, 2016.
- Copyright ©2016, American Association for Cancer Research.